The overall goal of this project is to establish and validate the optimal biochemical endpoints for the therapy of acromegaly. In acromegaly, chronic GH and IGF-I excess lead to multi-system manifestations, marked disability and a shortened life span. With modern methods for biochemical evaluation and new medical therapies, in particular long acting somatostatin analogs and the GH antagonist, pegvisomant, we may be able to improve outcome in acromegaly. However, we need to refine our current understanding of the optimal targets for therapy of acromegaly so that we can gauge "GH sufficiency", but also identify mild GH excess and prevent GH deficiency due to treatment. The aims of this project address this need. The first specific aim is to establish those levels of serum IGF-I and GH that will normalize long term outcome in acromegaly. We will establish criteria for GH suppression after oral glucose with a highly sensitive GH assay that may predict postoperative disease recurrence and validate IGF-I as a marker of disease activity based on comparison to morbidity and mortality outcomes. The second aim is to examine serum IGF-I level as a marker of disease control by assessing metabolic abnormalities, in particular insulin resistance, and body composition, a clinical marker of GH action in acromegaly, in relation to specific IGF-I levels during treatment with the potent GH antagonist, pegvisomant. It is our hypothesis that these combined assessments will give us a sensitive index by which we can gauge optimal IGF-I goals for therapy. The third aim is to compare somatostatin analog vs. pegvisomant therapy in a randomized study of patients with active acromegaly in order to determine which therapy is optimal in terms of normalizing IGF-I levels and insulin sensitivity. The fourth aim is to study the secretion of ghrelin, the newly identified hormone strongly linked to nutritional state and the GH axis, in acromegaly. Dysregulated ghrelin secretion and further ghrelin changes with therapy may be related to metabolic and biochemical abnormalities and could impact on body composition in acromegaly. Our work to date has firmly established a uniquely large cohort of patients with acromegaly and set the groundwork for this project. The experience of the PI in developing and evaluating this cohort and her clinical experience with these new medical therapies as well as the expertise of the collaborative research team covering areas of body composition analysis, insulin action, biostatistics and pituitary surgery make the team well equipped to accomplish the aims of this proposal.